Pharmacology 4 - Lipid Metabolism and Cardiovascular Disease Flashcards
How are non-polar lipids transported in the blood?
As cholesterol esters or triglycerides within lipoproteins
These lipoproteins can be:
- High density lipoprotein (HDL)
- Low density lipoprotein (LDL)
In regards to both HDL and LDL, what is cardiovascular disease (atherosclerosis) associated with?
Elevated LDL
Decreased HDL
In general terms, what does the statin class of drugs do?
Increases the ration of HDL to LDL
What are the two main causes of a low HDL to LDL ratio?
- Diet and lifestyle
- Genetic factors
What are lipoproteins?
Spherical particles with a hydrophobic core and hydrophilic coat formed by a monolayer of amphipathic molecules such as cholesterol, phospholipids and apolipoprotein
What is the role of apolipoprotein in a lipoprotein?
To stabilise the outer shell and act as a molecular address by mapping certain lipoproteins to certain body regions
What are the major lipoproteins? (4)
- HDL - contains apoA1 and apoA2
- LDL - contains apoB-100
- Very low density lipoprotein (VLDL) - contains apoB-100
- Chylomicrons - contains apoB-48
What is the purpose of apo-B containing lipoproteins?
Deliver triglycerides to muscle or fat tissue to be broken down for energy (muscle) or storage by forming adipose tissue from triglycerides (adipocytes)
Which cells produce chylomicrons?
Enterocytes (intestinal cells)
Chylomicrons are important for what, and since their triglyceride originates from outside the body this is what type of pathway?
Important for transporting dietary triglycerides to muscle
This is an exogenous pathway
Where are VLDLs produced?
Liver
What is the purpose of VLDL, and which type of pathway does it involve regarding triglycerides?
They are formed in liver cells and transport triglycerides synthesised there around the body
This is the endogenous pathway (triglycerides originate from within the body)
Describe the three steps of apoB containing liposomes
- Assembly - incorporation with apoB100 (liver) or apoB48 (intestine)
- Intravascular metabolism - lipoprotein lipase attacks the triglyceride component generating 3 fatty acids which can be taken up into fat or muscle cells
- Receptor mediated clearance
What are triglycerides broken down into when they pass through the enterocyte wall of the intestine?
Broken down to monoglyceride and 3 fatty acids
This is because trigllycerides cannot pass through the epithelium otherwise
What happens after the components of a triglyceride has passed across the membrane of the enterocyte?
The triglyceride is resynthesised
How does cholesterol pass across the enterocyte membrane?
Specific transport protein
Nienmann-Pick-C1-like 1 protein (NPC1L1)
Where does cholesterol mostly come from?
Liver (75%)
Diet (25%)
What happens to the cholesterol when it enters enterocytes?
It is esterified
When many triglycerides enter the cytoplasm of the enterocte, what happens next?
The triglyceride core is coated with apoB48 by ribosomes
Microsomal triglyceride transfer protein aids the addition of more triglycerides which form droplets called chylomicrons
At which point is a mature chylomicron formed in the enterocyte?
When both triglyceride and cholesterol ester have been added
What happens to a mature chylomicron when apoA1 is added in the enterocyte?
Exocytosis occurs and the chylomicrons exit the cell via the lymphatic system
They enter the central lacteal in the intestinal villus which allows them to be carried to the subclavian veins where they can enter the systemic circulation
What are VLDL particles formed and what from?
Liver from triglycerides
From which two sources can triglycerides come from?
- Breakdown of adipose tissue
- De nove synthesis in the liver
Before chylomicrons and VLDL particles can offload triglyceride and cholesterol, what must happen?
They must become activated
This involves apoCII, from HDL, being incorporated into the shell of LDL and chylomicrons
ApoCII facilitates binding between chylomicrons and VLDL to lipoprotein lipase which allows hydrolysis to occur
What happens to the ratio of cholesterol to triglyceride content as hydrolysis of the lipoprotein occurs?
It increases
Triglyceride is hydrolysed, by cholesterol concentration stays the same
After the triglycerides are all “used up” after hydrolysis, what are the remaining structures of chylomicrons and VLDLs called?
Chylomicron and VLDL remnants
At which point does lipoprotein lipase dissociate from either VLDL or chylomicrons?
When the cholesterol concentration becomes very high in comparison to the triglceride content
When lipoprotein lipase dissociates from VLDL or chylomicrons, what happens to apoCII?
It returns to HDL
After apoCII returns to HDL from chylomicrons and VLDLs what is it replaced with and why?
ApoE
This acts as a high affinity ligand for receptos in the liver which faciliates clearance of the remnants
What happens to chylomicrons and VLDL remnants in the liver?
They are further metabolised in the liver by hepatic lipase to remove any additional triglycerides
All apoB48 containing remnants and half of apoB100 remnants are cleared by receptor-mediated endocytosis in the liver